ABSTRACT After decades of improvement, premature mortality is uniquely on the rise in the U.S. among White non- Hispanic adults with low education. Suicide, drug poisoning (particularly from opiates), and alcoholic liver disease appear to be the culprits and have been coined ?deaths of despair.? Suicidal thoughts and behaviors, illicit drug use, and alcohol problems (or ?diseases of despair,? DoD)?the conditions that likely precede these deaths?are the focus of this application, as are the pathways to these DoD. Despite many years of research and in the face of rising suicides and a nationwide opiates public health emergency, we lack accurate and appreciable predictions of who will succumb to DoD and who will be shielded from them. Speedy new insights on the development of DoD are needed to inform efforts to reverse the rising tide of DoD. These can only be generated with decades' worth of prospective-longitudinal data with rich coverage of multiple levels of risk and protective factors?from community contexts to molecular mechanisms?with clinically-relevant characterizations of DoD. Realistically, no single extant dataset can fulfill these requirements. Secondary data analysis of multiple long- term longitudinal studies of recent cohorts, with recent young adult assessments, can provide an unprecedented opportunity here. We capitalize on three complementary, long-standing, prospective- longitudinal data sets spanning childhood, adolescence, and young adulthood, with recent assessments in young adulthood. (1) The nationally representative National Longitudinal Study of Adolescent to Adult Health (Add Health) allows for fine-grained socio-structural characterizations of individuals and communities affected by DoD. (2) The community-representative psychiatric-diagnostic Great Smoky Mountains Study (GSMS) was collected in mostly impoverished rural communities in Appalachia?one of the epicenters of the DoD epidemic. It features a quasi-experiment that allows testing for whether cash transfers?received by a subgroup of participants for over 15 years?are protective against DoD. (3) Fast Track is a comprehensive 10- year randomized clinical intervention trial with 15 years of follow-up data that targeted mechanisms that are key in recent models of pathways to DoD. The first aim is to look longitudinally at the developmental epidemiology of DoD across the early lifespan in the nationally-representative Add Health and in the rural- Appalachian GSMS with a large American Indian subsample. The second aim is to test a childhood/adolescent strain ? young adult social/economic disengagement ? despair ? DoD pathways model and also to test protective factors that could intervene on each pathway. We will also use discovery-focused machine learning algorithms to uncover new pathways to DoD in Add Health and GSMS. The third aim is to assess the impact of childhood interventions on DoD in GSMS and Fast Track.